Heart failure is a major public health challenge. Exercise is increasingly recognized as a powerful tool to mitigate adverse outcomes in heart failure. One key component of exercise is episodic heart rate acceleration interspersed with periods of rest. Although slower average heart rates have been consistently associated with improved cardiovascular outcomes, preliminary results indicate that exercise-similar episodes of heart rate acceleration above the baseline heart rate can serve as a trigger for upregulation of cardioprotective molecules and pathways associated with myocardial conditioning and remodeling. This stimulus, paired with much longer intervening periods of slower HRs to provide the opportunity and resources for adaptation, could be harnessed for therapeutic use. Specifically, an ?exercise-inspired? pattern of heart rate acceleration is delivered by a pacing protocol specially designed to be maximally physiologic and to confer positive myocardial adaptive stimuli while carefully avoiding known detrimental consequences of pacing. In mice, this pacing approach results in significant upregulation of cardioprotective ATP-sensitive potassium channels and inhibition of basal calcium/calmodulin-dependent protein kinase II activation. These molecular findings are coupled with improved resistance to ischemia/reperfusion injury and, in hearts recovering from infarct, less fibrosis. In 8 human subjects with chronic, medically treated but refractory systolic heart failure and left ventricular ejection fraction <=35%, reproduction of the pacing pattern, delivered through manual programming of the subjects? already-implanted pacing devices, transiently raises blood pressure and cardiac output and is both hemodynamically and symptomatically well-tolerated. In a pre-pilot, five such subjects were randomized in a single-blind fashion to the same pacing, or to sham pacing, performed daily for 3-5 days/week over 4 weeks. The pacing group reported significantly improved symptoms/quality of life over their baseline while improvement in the sham-treated group was not significant. Direct comparison between the groups showed a trend toward greater improvement with pacing vs. sham. These initial human studies support the safety and feasibility of the approach. Assessment of the impact on other functional and structural outcome measures will require greater cohort sizes. The proposed project will further investigate the molecular mechanisms of these observations in a mouse model of cardiomyopathy and in a human pilot study. Data obtained under this exploratory project, if supportive of the impact of the proposed pacing approach, will be used as preliminary data for a more intensive investigation for which NIH R01 funding will be sought. These studies have the potential to identify novel targets and strategies to promote cardioprotection and outcomes in heart failure. The approach has potential for high impact given that it may have broad applicability in an area of major medical need and be delivered using existing pacemaker hardware.